Dose and Treatment Selection in Clinical Trials

描述（由申请人提供）：新治疗的临床试验可能会通过三个阶段进行。I期试验通常是评估毒性并确定安全剂量范围的小型研究。具体的任务通常是确定最大耐受剂量。一旦选择了安全的治疗剂量，其治疗效果将在II期试验中进行测试。在II期试验中显示有希望的方案将被转移到大型的、多机构的III期研究中，将其有效性与标准治疗进行比较。在许多方案可能成为大型III期研究的候选方案，但相对于标准，可用于评价每种方案的资源太少的情况下，必须优先选择那些有希望在III期试验中成功评价的方案。在这项研究中，我们提出了新的统计设计和策略，以有效的方式利用观察到的临床数据，希望用更少的资源转化为同样准确的临床结论。具体而言，该应用程序涵盖以下三种临床场景。首先，我们提出了基于多个和重复的安全性终点的I期剂量探索试验的方法，并应用这些方法重新设计了当前的中风试验。现有的设计将终点分解为毒性或无毒的二分指标，并且可能以不利用所有可用信息为代价。我们提出的方法，预计将检索信息损失，通过使用所有的端点在进行试验。其次，我们提出了II期剂量探索疗效试验的方法，患者将分两个阶段入组。通过中期分析，我们可以关闭无效剂量，减少接受这些剂量治疗的患者数量。第三，我们提出了在II期试验中选择或筛选治疗的设计。目前的设计是僵化的，在规划和实施试验期间造成了很大的实际困难。例如，我们的方法在中期分析的时间安排和治疗的优先选择方面提供了灵活性。这些设计将应用于设计神经系统疾病患者的各种临床试验。尽管在过去的十年中的努力，急性缺血性中风和肌萎缩侧索硬化症（ALS）的其他治疗是迫切需要的。在成功完成这项研究后，我们将扩大我们的能力，以支持新疗法的早期研究，并提高各种临床试验环境中选择和筛选过程的统计效率。

DESCRIPTION (provided by applicant): Clinical trials of a new treatment may proceed through three phases. Phase I trials are typically small studies that evaluate toxicity and determine a safe dosage range. The specific task is usually to determine the maximum tolerated dose. Once a safe dose of the treatment is chosen, its therapeutic efficacy will be tested in a phase II trial. Regimens shown promising in phase II trials will then be moved to large, multi- institutional phase III studies that compare their effectiveness to standard treatments. In situations when many regimens are possible candidates for a large phase III study, but too few resources are available to evaluate each relative to the standard, priority must be set to select only those with promise for successful evaluation in phase III trials. In this research, we propose novel statistical designs and strategies that utilize the observed clinical data in an efficient manner, which is hoped to translate into equally accurate clinical conclusions with fewer resources. Specifically, this application covers the following three clinical scenarios. First, we propose methods for phase I dose-finding trials based on multiple and repeated safety endpoints, and apply the methods to re-design a current stroke trial. Existing designs collapse the endpoints into a dichotomized indicator of toxicity or no-toxicity, and may do so at the expense of not utilizing all information available. Our proposed methods are expected to retrieve the information loss by using all endpoints in the conduct of a trial. Second, we propose methods for phase II dose-finding efficacy trials, in which patients will be enrolled in two stages. Having an interim analysis, we can shut down ineffective doses and reduce the number of patients treated at these doses. Third, we propose designs to select or screen treatments in phase II trials. Current designs are rigid and impose great practical difficulty during the planning and the implementation of a trial. Our methods provide, for instance, flexibility in the scheduling of interim analyses and the prior preference of treatments. These designs will be applied to design various clinical trials in patients with neurological disorders. Despite the efforts in the past decade, additional therapies for acute ischemic stroke and amyotrophic lateral sclerosis (ALS) are sorely needed. Upon successful completion of this research, we will extend our capacity to support early phase investigation of new treatments and enhance the statistical efficiency of selection and screening process in a variety of clinical trial settings.